Pneumonia caused by Schizophyllum commune in a patient with diabetes: A case report and comprehensive literature review

Rationale: Schizophyllum commune (S. commune) is a basidiomycete bracket fungus that rarely causes invasive fungal infections. It is often misdiagnosed as other invasive fungal disease because of its atypical clinical features. Here we report a case of pneumonia due to S commune and review the relevant literature. Patient concerns and diagnoses: A 55-year-old male with a history of diabetes and poor glycemic control presented with cough and sputum for half a month. Laboratory examination showed elevated peripheral blood eosinophils, bronchoalveolar lavage fluid eosinophils and increased serum total immunoglobulin E. Chest computed tomography revealed a gloved finger sign and consolidation in the middle lobe of the right lung and the upper lobe of the left lung. Bronchoscopy revealed thick white mucous plugs in the left lingular bronchus, which could be removed partially by suctioning. The culture of bronchoalveolar lavage fluid and bronchoscopy brush specimens grew cottony white mold in sabouraud dextrose agar. Pneumonia caused by S. commune was diagnosed based on clinical features and microbial methods. Interventions and outcomes: Voriconazole combined with inhaled budesonide and formoterol (inhaled corticosteroids + long-acting β-2 receptor agonist) were given, and his symptoms improved. The count of peripheral blood eosinophils and serum total immunoglobulin E decreased after 1 month. Repeated chest computed tomography showed remarkable improvement over the previous lesions. Lessons: Although rarely reported, infections in the lungs caused by S commune should be reminded especially in patients with immunocompromised. This case illustrates the risk factors, clinical symptoms and imaging features of the pneumonia caused by S. commune. It also further highlights the diagnosis and treatment of this disease through reviewing relevant literature.


Introduction
Schizophyllum commune (S. commune) is an occasional pathogen which associated with immunocompromised patients such as diabetes, hematological malignancies, long-term used of immunosuppressant and structure lung diseases. [1,2] Few of cases have been reported worldwide since 1950 and most of cases were the form of case report. [3] Respiratory tract is one of the most vulnerable organs to S. Commune infections resulting in sinusitis, allergic bronchopulmonary mycosis (ABPM) and pneumonia which is closely related to continuous inhalation of fungal hyphae. Despite of the increasing number of cases of S. Commune infections to pulmoanry recent years, most cases were reported from Japan. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] In addition, there is still unclear about the clinical presentation, imaging, therapeutic agents and prognosis of pneumonia to S. Commune. We herein reported a rare case of pulmonary mycosis due to S. Commune in a diabetic patient and relevant published global literature were also reviewed. The study was approved by the Institutional Ethics Board of Shaoxing People's Hospital and the patient has provided informed consent for publication of the case. Medicine

Case report
A 55-year-old male with a history of diabetes and poor glycemic control presented to our hospital with cough and sputum for half a month. He has been smoking for 50 years. What's more, he had been come to our outpatient for persistent cough and sputum 6 years ago. Laboratory test showed white blood cell count of 7.7 × 10 9 /L with 8.4% of eosinophils at that time. Chest computed tomography (CT) showed gloved finger sign, consolidation in the middle lobe of the right lung and upper lobe of the left lung (Fig. 1A). He was prescribed with cefuroxime for 14 days and the symptoms improved. Unfortunately, he was lost to follow-up later. On admission, no abnormal signs identified. Laboratory test revealed white blood cell count of 4.02 × 10 9 /L with 18.8% of eosinophils, elevated absolute eosinophil count of 0.76 × 10 9 /L and high total serum immunoglobulin E (IgE) level (327 KU/L). Serum biochemistry, β-D-1,3-glucan, cryptococcus serum antigen, interferon-gamma release assays, C-reactive protein and respiratory pathogens testing was normal. Pulmonary function test indicated neither asthma nor chronic obstructive pulmonary disease. Chest CT disclosed a patchy of consolidation, infiltrates and gloved finger sign in the left lingular lobe (Fig. 1B). PET/CT showed mild metabolic activity in the left lingular lobe which consistent with inflammation indicating the exclusion of malignancy (Fig. 1C). Bronchoscopy showed mucosal swelling and thick white mucous plugs in the left lingular bronchus which could be removed partially by suctioning (Fig. 1D). The eosinophils of bronchoalveolar lavage fluid (BALF) was 10% and culture of BALF was performed. Differential diagnosis of ABPM or allergic bronchopulmonary aspergillosis and other infectious diseases should be considered owing to elevated serum eosinophil count, high total IgE and mucous plugs in bronchus.
The culture of BALF and brush demonstrated filamentous, and cottony white mold grew in sabouraud dextrose agar both of BALF and bronchoscopic brush specimens ( Fig. 2A). Large amounts of eosinophils were seen in biopsied tissue with hematoxylin and eosin stain (Fig. 2B). Nucleotide sequencing (18S rRNA) identified this fungus as S. Commune. Antifungal susceptibility test of the culture of BALF was performed using the broth micro dilution method according to the Clinical and Laboratory Standards Institute. Minimum inhibitory concentrations of antifungal agents was presented in Table 1. He was given voriconazole combined with inhaled corticosteroids/ formoterol long-acting β-2 receptor agonist. One month after treatment, his symptoms disappeared and the level of peripheral blood eosinophils, serum total IgE decreased. Repeated chest CT showed remarkable absorption of the previous lesion. He continued the original treatment for 3 months and neither side-effect of drugs nor recurrence occurred.

Discussion
Aspergillus is one of the most common opportunistic pathogens associated with morbidity and mortality in immunosuppressed patients worldwide. [19] Nonetheless, the incidence of rare mold infections other than aspergillosis have been gradually increased owing to the widespread use of antibiotics and antifungal agents. [20] Schizophyllum commune (S. commune) is a fungi of Basidiomycete which commonly existed in rotting wood and leaves. [1,21] Infections due to S. commune was first reported by Kligman in 1950. [22] It is an opportunistic pathogen that yield to the patients according to the age, immune status and the load of the pathogens in the host. Respiratory tract (especially lungs) is the major target of S. commune. [12] Previous studies [1,21] showed the incidence of infections caused by S. commune might be underestimated because of unawareness of this specimen and the difficulties in laboratory identification. Herein, literature search was performed using the databases of "Pubmed," "Medline" and "Web of science" and using the search strategy: "Pulmonary" or "Lung" combined with "Schizophyllum commune" from 1994 to 2022. A total of 23 articles and 25 cases were enrolled (Table 2). In addition, there were several reports in Japanese which were excluded because of not available of the full text.
Most of the cases (60%, n = 15) were from Japan suggesting Japan was more concerned about this pathogen. However, few of cases were reported in China. Nearly 2 thirds of the patients (16 of 25) had certain underlying conditions. The patient we present also had a history of diabetes and poor glycemic control which was a high-risk factor of S. commune infection. The main clinical symptoms were atypical, including cough, sputum, wheezing, dyspnea and hemoptysis. Four patients were asymptomatic and found in routine medical examination. As to laboratory examination, nearly half (12/25) of the patients showed elevation of eosinophils, 7 of 25 patients showed increased serum total IgE, 10 of 25 patients revealed elevation of serum antibody to S. commune (including specific IgE and IgG).In addition, elevated serum aspergillus fumigatus IgG and/ or serum aspergillus fumigatus IgE in ABPM due to S. commune were found in some cases, which might be related to the presence of antigenic cross-reactivity between S. commune and aspergillus fumigatus. [11,14] The imaging of chest CT of pneumonia caused by S. commune can be classified into followings according to the literature: Mucous plugs or glove finger sign. These were the most common manifestation; Pulmonary fungal balls or uniformly dense strips. That might be the result of the growth of S. commune on the basis of the exsisting pulmonary cavity; Pulmonary atelectasis, caused by complete blockage of bronchus by mucous plugs; Consolidations or infiltrates; Pleural effusion. While someone with normal chest CT mainly presented with airway hyperresponsiveness. [10] As to our case, chest CT showed gloved finger sign and consolidation in the bilateral lungs 6 years ago. Combined with clinical symptoms, high eosinophils and CT image, infection of S. commune should be suspected at that time, despite no further examination performed. The typical manifestation of bronchoscopy was jelly-like substances or mucus plug in the bronchial lumen which could not be removed by forceps or suction causing obstruct the bronchus and/or local pulmonary atelectasis in several cases. [9,15,18,21] The diagnosis of pneumonia of S. commune was mainly based on the culture of respiratory or postoperative lung specimens. [3] While negative culture results have also been reported and serum antibody to S commune is helpful. [11] Recently, accurate identification has been increasingly achieved by molecular methods using nucleotide sequencing of the internal transcribed spacer, 18S rRNA gene and/or large subunit rRNA gene. [1,26] While metagenomic next-generation     sequencing is gradually applied in the detection of S. commune. [12] It can be misdiagnosed as invasive pulmonary aspergillosis or allergic bronchopulmonary aspergillosis/ABPM because of the similar clinical manifestations and imaging. [4] In our case, pathogen of S. commune was cultured in both sputum and BALF, although elevated serum eosinophil count and high total IgE and mucous plugs, the diagnostic criteria of ABPM was not met. [27] The optimal antifungal therapy and the course of treatment have been limited. Both itraconazole and voriconazole were successfully used, while a part of cases achieved good results with fluconazole and amphotericin B. It had reported that voriconazole had good curative effect on S. commune infection and could be used as a rescue therapy for ineffective of itraconazole. [12,14] In addition, there is currently no guideline recommendation on antifungal agents in combination with systemic or inhale corticosteroid. Based on previous literature, if one had symptoms such as shortness of breath, wheezing, dyspnea, elevation of blood eosinophils and serum total IgE, combined systemic or inhale corticosteroid was recommended but not alone. The duration of the treatment for S. commune infection is not standardized ranging from 1 month to 1 year, and usually 3 to 4 months suggesting individualized treatment course was considered. The prognosis of pulmonary of S commune infection is well. Only 1 ptatient in literature review died which may be associated with her advanced age, underlying diseases and a wide range of lesions involved. [26]

Conclusion
In conclusion, clinicians should pay great attention to pulmonary infections caused by S. commune especially in immunocompromised patients despite few cases have been reported. Azole antifungals are the preferred agents for S. commune infection. Good prognosis will be achieved under proper antifungal therapy and the course of the treatment should be individualized.